This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent moiety is an indol-3-yl-alkyl group and the other moiety is an alkoxy-substituted pyrimidin-4-yl ring. These compounds possess a unique serotonergic profile that renders them useful in treatment of vascular headaches such as migraine.
Archer disclosed a large series of CNS-depressant indolylalkylpiperazines in U.S. Pat. No. 3,188,313. Among a large number of possible substituents on the 4-nitrogen atom of the piperazine ring was pyrimidine (unsubstituted). In U.S. Pat. No. 3,562,278, Archer disclosed and claimed a series of 1-indolylethyl-4-substituted-piperazines. Among the possible 4-substituents listed is 2-pyrimidinyl, again unsubstituted. The pharmacologic action disclosed for these art compounds is general CNS and psychomotor depression which bear no relationship to an antimigraine. Thus the compounds of Archer do not suggest the alkoxypyrimidine antimigraine compounds of this invention.
Dowie, et al. disclosed a series of 3-alkylaminoindole derivatives as being potentially useful for the treatment of migraine in a published patent application, GB 2,124,210. One member of this series of compounds was specifically claimed in a later patent application of Oxford, GB 2,162,522, published Feb. 5, 1986. This particular compound is known in the literature as sumatriptan.(1) ##STR2##
A series of novel indoline derivatives were disclosed Feb. 7, 1990 by Manoury, et al., in European patent application EPA 354,094. These compounds are described as being useful for treatment of various CNS disorders including depression, anxiety and migraine. Included among these art compounds are those of formula (2) ##STR3## wherein R.sup.4 is aryl, pyridine or quinoline moieties.
None of these art compounds make obvious the instant novel indol-3-ylalkyl derivatives of alkoxypyrimidinylpiperazine for treatment of vascular headaches such as migraine.
Migraine is a member of a broader class of headache which also comprises cluster headaches and other headaches believed to have a vascular implication in their etiology. These headaches are classified as vascular headaches. For a current summary of headache and its treatment see: Chapter 13: "Drugs Used to Treat Migraine and Other Headaches" in Drug Evaluations, 6th Edn., 1986, pages 239-253 American Medical Association, W. B. Saunders Co., Philadelphia, Pa.
Frequent irregularly-occurring episodes of headache afflict a large number of people but are usually acute in nature and of short duration. Relief of this type of headache is typically provided by mild analgesics such as aspirin or acetaminophen. Such headaches are quite common and, while painful and perhaps annoying, are seldom incapacitating and debilitating. Chronic recurrent headaches of the vascular category, however, usually lead to patient consultation with a physician due to pain severity which is often incapacitating.
Although there is no universally accepted classification system for headache, vascular headache, for the purposes of the present invention, refers mainly to migraine and cluster headaches. Migraine includes the common or classical type as well as migraine variants which would be familiar to one skilled in the art. Other subtypes such as toxic vascular and hypertensive headaches, chronic paroxysmal hemicrania, as well as some muscle-contraction and combined or mixed vascular-muscle headaches may also fall into a vascular-related headache category and be treatable by the present invention. It is appreciated by one skilled in the art that no single therapy is effective in all patients diagnosed with the same subtype of headache, thereby raising further uncertainties about headache classification.
Drugs most commonly used in treatment of headache fall into the following groups:
Ergot Alkaloids,
Beta-blocking Agents,
Calcium Channel Blocking Agents,
Antidepressants, and
Mixtures of these.
Management of recurring vascular headache is complicated by the lack of a single therapy which is effective in all patients with the same headache type and by the need to select either an abortive or prophylactic method of treatment for these headaches. Further complication involves the current use of drugs that cause dependence with extended use, such as ergotamine. Another important consideration for the present invention is that the more effective antimigraine agents in current use, e.g. the ergots, methysergide, produce severe use-limiting side-effects with long term usage.
Thus there is a need for a safe and effective drug for the treatment of migraine and related disorders which can be used either prophylactically or to alleviate an established headache.
The objectives of the present invention relate to the use of novel indol-3-ylalkyl derivatives of alkoxypyrimidinylpiperazines to provide treatment of vascular headaches, particularly migraine; to processes for their preparation; and to their pharmaceutical compositions and medical usage.